CN107091930B - Method for rapidly predicting and improving sensitivity of non-small cell lung cancer cells to epidermal growth factor receptor inhibitor - Google Patents
Method for rapidly predicting and improving sensitivity of non-small cell lung cancer cells to epidermal growth factor receptor inhibitor Download PDFInfo
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Abstract
The invention provides a method capable of quickly predicting and improving the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor, which predicts the sensitivity of NSCLC to an EGFR inhibitor by detecting the activation level of a PERK channel in UPR (epithelial cell receptor), namely the phosphorylation degree of eIF2a protein and the expression level of ATF4 protein, and improves the sensitivity of the lung cancer cells to the EGFR inhibitor by inhibiting the activation level of the PERK channel in the UPR.
Description
Technical Field
The invention relates to the field of biotechnology, in particular to a method capable of quickly predicting and improving the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor.
Background
Lung cancer is the most serious malignant tumor with global incidence and fatality, and its 5-year survival rate is less than 20% despite the current methods of chemotherapy, radiotherapy, targeted therapy and immunotherapy (Allemani C, Weir HK, Carreira H, et. Global therapeutic and of coronary Survival 1995-2009: Lancel,2015,385(9972), 977-1010). Non-small cell lung Cancer (NSCLC) is the most common type of lung Cancer, accounting for about 80% (Lin Y, Wang X, Jin H. EGFR-TKI resistance on NSCLC patients, mechanisms and strategies, Am J Cancer Res,2014,4(5), 411-435). Epidermal Growth Factor Receptor (EGFR) inhibitors are currently one of the most prominent drugs for targeted therapy of non-small cell lung cancer (NSCLC). Most NSCLC patients are receiving first generation EGFR inhibitors (e.g., Ge)fitinib and Erlotinib) can cause drug resistance. Of these, approximately 10% to 15% of patients have drug resistance due to mutations in the EGFR molecule or other kinases such as Anaplastic Lymphoma Kinase (ALK) on tumor cells that have become resistant (e.g., EGFRT790M) This fraction of patients may be alleviated by administration of second or third generation EGFR inhibitors. However, the mechanism of resistance to EGFR inhibitors in more than 80% of NSCLC patients remains unclear, and methods for enhancing the sensitivity of this group of patients to EGFR inhibitors are lacking.
The Unfolded Protein Response (UPR) is a series of evolutionarily well-conserved signaling pathways aimed at maintaining proper folding and functional conformation of proteins following synthesis in the intracellular Reticulum (ER). The pathway consists essentially of three branches, IRE1, PERK and ATF6 pathways. Wherein IRE1, upon activation, cleaves and activates the transcriptional activity of XBP 1; PERK, when activated, phosphorylates eIF2 α, which enhances translation of ATF4 protein; ATF6 can be transported to the golgi by specific transporters, cleaved and activated on the golgi membrane. When the three pathways are activated, the three pathways can transmit the effect of causing cell survival or apoptosis through the expression of downstream molecules such as GRP78, CHOP and the like.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for rapidly predicting and improving the sensitivity of non-small cell lung cancer cells to epidermal growth factor receptor inhibitors. The method of the invention can quickly predict the sensitivity of NSCLC patients to EGFR inhibitors and improve the sensitivity of NSCLC patients to EGFR inhibitors. The technical scheme provided by the invention is as follows.
A method for rapidly predicting the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor predicts the sensitivity of NSCLC to an EGFR inhibitor by detecting the activation level of a PERK pathway in UPR (blast-resistant cell receptor) cells, namely the phosphorylation degree of eIF2a protein and the expression level of ATF4 protein.
It is another object of the present invention to provide a method for increasing the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor by inhibiting the level of activation of the PERK pathway or the expression of ATF4 protein in UPR.
Specifically, the method for improving the sensitivity of the non-small cell lung cancer cell to the epidermal growth factor receptor inhibitor is to reduce the expression of PERK or ATF 4.
The preferred method for increasing the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor is the use of a small molecule inhibitor of PERK in combination with an EGFR inhibitor.
Preferably, the EGFR is Erlotinib.
By the method, the sensitivity of the non-small cell lung cancer cell to the epidermal growth factor receptor inhibitor can be quickly predicted and improved.
English letters explain:
gefitinib, Gefitinib
Erlotinib, Erlotinib
IRE1(inositol-requiring enzyme 1), inositol-requiring enzyme-1
PERK (protein kinase R-like ER kinase), protein kinase R-like endoplasmic reticulum kinase
ATF6(Activating transcription factor 6), Activating transcription factor 6
XBP1(X-box binding protein 1), X-box binding protein 1
eIF2 alpha (Eukaryotic Initiation Factor 2), Eukaryotic Initiation Factor 2
ATF4(Activating transcription factor 4), Activating transcription factor 4
GRP 7878 kDa (78kDa glucose-regulated protein), glucose regulatory protein.
Drawings
FIG. 1 is a graph showing the results in example 1 of the present invention;
FIG. 2 is a graph showing the results in example 2 of the present invention;
FIG. 3 is a graph showing the results of example 3 of the present invention;
FIG. 4 is a graph showing the results of example 4 of the present invention;
FIG. 5 is a graph showing the results in example 5 of the present invention;
FIG. 6 is a graph showing the results of example 6 of the present invention;
FIG. 7 is a graph showing the results in example 7 of the present invention.
Detailed Description
The following are examples of the present invention, which are not intended to limit the scope of the present invention.
Example 1
The semi-lethal concentration of Erlotinib treatment in 9 NSCLC cell lines was determined by the "concentration-effect" method under in vitro cell culture conditions (EC 50).
The experimental method comprises the following steps:
1.9 NSCLC cells H322, H358, H441, Calu3, A549, H1703, SW1573, H460 and H23 were cultured in RPMI1640 medium (supplemented with 10% fetal bovine serum, 10unit/ml penicillin and 10unit/ml streptomycin). The culture conditions were 37 ℃ and 5% CO2. Erlotinib was dissolved in DMSO at a stock concentration of 10 mM.
2. On 96-well cell culture plates, 10 cells were seeded at a density of 3000 cells/well. 24 hours after cell planting, the cells were treated with Erlotinib at concentrations of 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M, 0.625. mu.M, 0.3125. mu.M, 0.156. mu.M, 0.078. mu.M and 0. mu.M (DMSO). After 72 hours of treatment, cell viability assays were performed using CellTiter Glo reagent and "concentration-effect" calculations were performed using Prism software to determine the semi-lethal concentration of Erlotinib treatment by 9 cells (EC 50). The experimental results are as follows: see fig. 1a and b.
Example 2
Data for eIF2 α phosphorylation, eIF2 α overall levels, ATF4 expression levels and internal reference GAPDH were obtained in 9 NSCLC cell lines by Western blotting techniques (Western blotting). Then, correlation analysis is carried out on the expression quantity of the protein and the EC50 concentration of the respective cell strain on the Erlotinib, and the levels of phosphorylated eIF2 alpha and ATF4 are found to be remarkably related to the EC50 of the cell on the Erlotinib: the higher the phosphorylation level of eIF2 α, the higher the expression level of ATF4, and the lower the sensitivity of lung cancer cells to Erlotinib (the higher EC 50).
The experimental method comprises the following steps:
1.9 NSCLC cells H322, H358, H441, Calu3, A549, H1703, SW1573, H460 and H23 were cultured in RPMI1640 medium (supplemented with 10% fetal bovine serum, 10unit/ml penicillin and 10unit/ml streptomycin). The culture conditions were 37 ℃ and 5% CO2。
2. The standard RIPA buffer (20mM Tris-HCl (pH 7.5),150mM NaCl,1mM Na) was used2EDTA,1mM EGTA, 1% NP-40, 1% sodium deoxyholate, 2.5mM sodium pyrophosphate,1mM beta-glycophosphophosphate, 1mM Na3VO4, 1. mu.g/ml leupeptin, 1mM PMSF) cell lysates of the above 9 cells were collected on ice. The protein concentration of the lysate was measured by Bradford method and 1. mu.g/. mu.l of protein lysate was prepared from RIPA buffer, 350mM DTT, 25% glycerol, 2% SDS, 0.01% Bromophenol Blue. Heating at 75 deg.C for 10 min.
3. The phosphorylation level of eIF2a, the expression level of eIF2a, the expression level of ATF4 and the expression level of GAPDH in the protein sample of the above 10 cell lines were measured by the Western Blotting method.
1) Separating protein by SDS-PAGE (gel concentration of 10%);
2) transferring the protein to a nitrocellulose membrane;
3) blocking with TBST buffer containing 5% skimmed milk for 1 hour at room temperature;
4) primary antibody incubation: anti-phosphorylated eIF2 α (Cell Signaling technology #9721), anti-total eIF2 α (Cell Signaling technology #5324), anti-ATF 4(Cell Signaling technology #11815), anti-GAPDH antibody incubated for 12 hours at 4 ℃;
5) incubation was performed with a secondary antibody conjugated to the corresponding horseradish peroxidase to the primary antibody for 1 hour at room temperature.
6) Using SuperSignalTMWest Pico chemiluminescent substrate was developed and exposed on film. The intensity of the protein band in each sample after the film was scanned with an Epson scanner was quantified with ImageJ software.
4. The expression of the above proteins and the EC50 of Erlotinib in the respective cells were analyzed by Prism for Pearson correlation to obtain the corresponding correlation coefficients and statistical significance.
The experimental results are as follows:
levels of phosphorylated eIF2 α and ATF4 were significantly correlated with EC50 of the cells against Erlotinib: the higher the phosphorylation level of eIF2 α, the higher the expression level of ATF4, and the lower the sensitivity of lung cancer cells to Erlotinib (the higher EC 50). The results are shown in FIGS. 2A, B and C.
Example 3
The 4 lines of cells H322, H441, A549 and H460 are planted under the skin of a nude mouse to form tumors, and the Erlotinib treatment is carried out after two weeks of planting, so as to obtain the data (TGI value) of the degree of inhibition of the four lines of cells by Erlotinib in the process of forming tumors. Then, the phosphorylation level of eIF2a and the expression level of ATF4 in the 4 strains of cells are correlated with the degree of Erlotinib inhibition of the 4 strains of cells in nude mice. The conclusion is that the phosphorylation level of eIF2a and the expression level of ATF4 are significantly related to the extent of response of cells to Erlotinib in nude mice.
The experimental method comprises the following steps:
the culture, maintenance and expansion of H322, H441, a549, and H460 cells were performed as in example 1. Collection 106The cells of (a) were injected subcutaneously into the right groin of nude mice (nude mice) of 8 weeks of age, 10 nude mice were injected per cell, after injection, 10 animals were randomly divided into two groups, group a was a control group, group B was an Erlotinib injection group, group B animals received intraperitoneal injection of Erlotinib suspension at a dose of 50mg/kg/d for the period from the third week to the sixth week after the animals were inoculated with tumor cells, group a animals were injected with physiological saline at the same time using the same injection method, and after six weeks after the animals were inoculated with tumor cells, tumors of each group were taken out, weighed, and the tumor inhibition rate was calculated by TGI (mean of group a-mean of group B tumors)/mean of group a tumors × 100%.
Pearson correlation analysis was performed using Prism software on eIF2a phosphorylation levels and ATF4 expression levels (results from example 1) of 4 cells and TGI values from 4 cells.
The experimental results are as follows:
the levels of phospho-eIF 2 α and ATF4 in the 4 above strains of cells were significantly negatively correlated with the TGI of Erlotinib: the higher the phosphorylation level of eIF2 alpha and the higher the expression level of ATF4, the lower the inhibition degree (TGI) of lung cancer cells by Erlotinib in nude mice, i.e., the lower the sensitivity. The results are shown in FIGS. 3A and B.
Example 4
Under the condition of in vitro cell culture, the expression level of PERK is reduced by an RNA interference technology, so that the phosphorylation level of eIF2a in H460 cells can be effectively reduced, and simultaneously, the EC50 of the cells during Erlotinib treatment is also reduced.
The experimental method comprises the following steps:
chemically synthesized small DNA fragments TGCATCTGCCTGGTTACTTAA (shPERK-1) and GTTGTGCTAGCAACCCTAATA (shPERK-2) were cloned into plko.1 plasmid using plko.1 (from addge, usa) empty plasmid. The above plasmids, including control empty plasmid (shControl), shPERK-1 and shPERK-2, were transfected into H460 cells by Lipofectamine2000 reagent, and the transfected H460 cells were screened with puromycin at a concentration of 2ug/ml, to obtain H460 cells (H460-shControl, H460-shPERK-1, and H460-shPERK-2) stably expressing the above plasmids. The expression level of PERK protein, phosphorylation level of eIF2a and expression level of GAPDH protein in H460 cells were determined using the western blot technique and quantitative method in example 2.
The Erlotinib treatment of example 1 was performed using the H460-shControl, H460-shPERK-1, and H460-shPERK-2 cells obtained above, and EC50 values of Erlotinib were obtained for the above cells.
The experimental results are as follows:
by comparing the results of the western blot experiment with the EC50 value, the PERK protein of H460 cells is reduced by RNA interference technology, and the level of phosphorylated eIF2a is reduced; meanwhile, the EC50 value of Erlotinib on cells is correspondingly reduced, which indicates that the cells become more sensitive to Erlotinib. See fig. 4A and B.
Example 5
Under the condition of in vitro cell culture, the expression level of ATF4 can be effectively reduced by RNA interference technology, so that the expression level of ATF4 in H460 cells can be effectively reduced, and the EC50 of the cells during Erlotinib treatment can be reduced.
The experimental method comprises the following steps:
chemically synthesized small DNA fragments CCACTCCAGATCATTCCTTTA (shaTF4-1) and GCCTAGGTCTCTTAGATGATT (shaTF4-2) were cloned into pLKO.1 plasmid using pLKO.1 (from Addge, USA). The above plasmids, including control empty plasmid (shControl), shATF4-1 and shATF4-2, were transfected into H460 cells by Lipofectamine2000 reagent, and the transfected H460 cells were screened with puromycin at a concentration of 2ug/ml to obtain H460 cells (H460-shControl, H460-shATF4-1, and H460-shATF4-2) stably expressing the above plasmids. Cell-to-CT kit and its program are used to extract mRNA from Cell and reverse transcribe the mRNA to obtain cDNA. Then, the mRNA level of ATF4 in H460 cells was detected by using fluorescent quantitative PCR technology using forward primer GACCACGTTGGATGACACTTG and reverse primer GGGAAGAGGTTGTAAGAAGGTG using Quantstrudio of ThermoFisher as fluorescent quantitative PCR instrumentTMSYBR Green was used for fluorescein, and the protocol for fluorescent quantitative PCR used the self-contained standard protocol of the instrument.
The Erlotinib treatment in example 1 was performed using the H460-shControl, H460-shATF4-1, and H460-shATF4-2 cells obtained above to obtain the EC50 value of Erlotinib against the above cells.
The experimental results are as follows:
fluorescent quantitative PCR detection of ATF4mRNA level shows that after ATF4 protein of H460 cell is reduced by RNA interference technology, EC50 value of Erlotinib to cell is correspondingly reduced, which indicates that cell becomes more sensitive to Erlotinib. See fig. 5A and B.
Example 6
Under the condition of in-cell and out-cell culture, the sensitivity of H460 cells to Erlotinib can be enhanced by adding a small-molecule inhibitor of PERK.
The experimental method comprises the following steps:
100,000H 460 cells were plated on 3.5cm diameter cell culture dishes and pretreated with a final concentration of 0.1. mu.M of a PERK small molecule inhibitor (GSK2656157 from EMD Millipore) for 48 hours. After pretreatment, untreated H460 control cells and H460 cells pretreated with PERK inhibitor were plated in 96-well plates as described in example 1, treated with Erlotinib at the same concentration gradient, and tested for cell survival, comparing EC50 values for Erlotinib for both cells. Meanwhile, according to the method in the example 2, control and pretreated H460 cells are collected and subjected to Western blotting detection, and the phosphorylation level of the PERK downstream gene eIF2a and the expression of ATF4 protein in the cells after the PERK small molecule inhibitor treatment are detected.
The experimental results are as follows:
after the pretreatment of the PERK small molecule inhibitor, eIF2a phosphorylation and ATF4 protein expression level of H460 cells are down-regulated; meanwhile, the EC50 value of Erlotinib killing cells was reduced by 60%. See fig. 6A and B.
Example 7
H460 cells are used for carrying out subcutaneous tumor formation experiments of nude mice, and tumor growth conditions in animals of each group are compared by carrying out four modes of A) control, B) PERK inhibitor treatment, C) Erlotinib treatment and D) PERK inhibitor and Erlotinib co-treatment, so that the PERK inhibitor can enhance the in-vivo tumor inhibition effect of Erlotinib.
The experimental method comprises the following steps:
the method of example 1 was used for the culture, maintenance and expansion of H460 cells. Collection 106The cells of (1) were injected subcutaneously into the right groin of 8-week-old nude mice (nude mice), and 40 nude mice were injected in total, after injection, 40 animals were randomly divided into four groups, group a was a control group (PBS-treated), group B was a PERK small molecule inhibitor GSK 2656157-treated group, group C was an Erlotinib-treated group, group D was a GSK2656157 and Erlotinib combined-treated group, GSK2656157 was at a treatment dose of 50mg/Kg/D, Erlotinib was at a treatment dose of 50mg/Kg/D, and the injection period was from the third week to the sixth week after the animals were inoculated with tumor cells.
The experimental results are as follows:
the use of a PERK inhibitor to reduce the activity of the PERK pathway may effectively increase the ability of Erlotinib to inhibit tumor growth in animals. See fig. 7.
Claims (4)
1. A method for rapidly predicting the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor is characterized in that the sensitivity of NSCLC to an EGFR inhibitor is predicted by detecting the activation level of a PERK channel in UPR (blast-resistant cancer cell receptor), namely the phosphorylation degree of eIF2a protein and the expression level of ATF4 protein, wherein the epidermal growth factor receptor inhibitor is Erlotinib.
2. A method for improving the sensitivity of non-small cell lung cancer cells to an epidermal growth factor receptor inhibitor improves the sensitivity of the lung cancer cells to the EGFR inhibitor by inhibiting the activation level of a PERK channel in UPR or inhibiting the expression level of ATF4 protein, wherein the epidermal growth factor receptor inhibitor is Erlotinib.
3. The method of claim 2, wherein the method is inhibition of expression of PERK protein or ATF4 protein.
4. The method of claim 2, wherein the method of inhibiting the level of activation of the PERK pathway in a UPR is the addition of a small molecule inhibitor of PERK.
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